The present invention relates to a process for preparing substituted pyridines which are intermediates in the synthesis of β-adrenergic receptor agonists useful as hypoglycemic and antiobesity agents, increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals. The β-adrenergic receptor agonists further possess utility in the treatment of intestinal motility disease disorders, depression, prostate disease, dyslipidemia and airway inflammatory disorders such as asthma and obstructive lung disease.
The disease diabetes mellitus is characterized by metabolic defects in production and/or utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
The β-adrenergic receptor agonists effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
The β-adrenergic receptor agonists also reduce body weight or decrease weight gain when administered to mammals. The ability of β-adrenergic receptor agonists to affect weight gain is due to activation of β-adrenergic receptors which stimulate the metabolism of adipose tissue.
β-Adrenergic receptors have been categorized into β1-, β2- and β3-subtypes. Agonists of β-receptors promote the activation of adenyl cyclase. Activation of β1-receptors invokes increases in heart rate while activation of β2-receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of β3-receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and metabolic rate (energy expenditure), and thereby promote the loss of fat mass. Compounds that stimulate β-receptors are, therefore, useful as anti-obesity agents, and can also be used to increase the content of lean meat in edible animals. In addition, compounds which are β3-receptor agonists have hypoglycemic and/or anti-diabetic activity, but the mechanism of this effect is unknown.
Until recently β3-adrenergic receptors were thought to be found predominantly in adipose tissue. β3-Receptors are now known to be located in such diverse tissues as the intestine (J. Clin. Invest., 91, 344 (1993)) and the brain (Eur. J. Pharm., 219,193 (1992)). Stimulation of β3-receptors have been demonstrated to cause relaxation of smooth muscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411 (1989); Br. J. Pharm., 112, 55 (1994); Br. J. Pharmacol, 110, 1311 (1993). For example, stimulation of β3-receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J.Pharm.Exp.Ther., 260, 1, 192 (1992).
The β3-receptor is also expressed in human prostate. Because stimulation of β3-receptors cause relaxation of smooth muscles that have been shown to express the β3-receptor (e.g. intestine), one skilled in the art would predict relaxation of prostate smooth muscle. Therefore, β3-agonists will be useful for the treatment or prevention of prostate disease.